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A Mutation in the S...
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Jagannathan, Vidhya
(author)
A Mutation in the SUV39H2 Gene in Labrador Retrievers with Hereditary Nasal Parakeratosis (HNPK) Provides Insights into the Epigenetics of Keratinocyte Differentiation
- Article/chapterEnglish2013
Publisher, publication year, extent ...
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2013-10-03
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Public Library of Science (PLoS),2013
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electronicrdacarrier
Numbers
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LIBRIS-ID:oai:DiVA.org:uu-220001
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https://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-220001URI
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https://doi.org/10.1371/journal.pgen.1003848DOI
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https://res.slu.se/id/publ/53585URI
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Language:English
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Summary in:English
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Subject category:ref swepub-contenttype
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Subject category:art swepub-publicationtype
Notes
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Hereditary nasal parakeratosis (HNPK), an inherited monogenic autosomal recessive skin disorder, leads to crusts and fissures on the nasal planum of Labrador Retrievers. We performed a genome-wide association study (GWAS) using 13 HNPK cases and 23 controls. We obtained a single strong association signal on chromosome 2 (p(raw) = 4.4x10(-14)). The analysis of shared haplotypes among the 13 cases defined a critical interval of 1.6 Mb with 25 predicted genes. We re-sequenced the genome of one case at 38x coverage and detected 3 non-synonymous variants in the critical interval with respect to the reference genome assembly. We genotyped these variants in larger cohorts of dogs and only one was perfectly associated with the HNPK phenotype in a cohort of more than 500 dogs. This candidate causative variant is a missense variant in the SUV39H2 gene encoding a histone 3 lysine 9 (H3K9) methyltransferase, which mediates chromatin silencing. The variant c.972T>G is predicted to change an evolutionary conserved asparagine into a lysine in the catalytically active domain of the enzyme (p.N324K). We further studied the histopathological alterations in the epidermis in vivo. Our data suggest that the HNPK phenotype is not caused by hyperproliferation, but rather delayed terminal differentiation of keratinocytes. Thus, our data provide evidence that SUV39H2 is involved in the epigenetic regulation of keratinocyte differentiation ensuring proper stratification and tight sealing of the mammalian epidermis.
Subject headings and genre
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Bannoehr, Jeanette
(author)
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Plattet, Philippe
(author)
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Hauswirth, Regula
(author)
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Droegemueller, Cord
(author)
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Droegemueller, Michaela
(author)
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Wiener, Dominique J.
(author)
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Doherr, Marcus
(author)
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Owczarek-Lipska, Marta
(author)
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Galichet, Arnaud
(author)
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Welle, Monika M.
(author)
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Tengvall, KatarinaUppsala universitet,Institutionen för medicinsk biokemi och mikrobiologi,Science for Life Laboratory, SciLifeLab(Swepub:uu)katst103
(author)
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Bergvall, KerstinSwedish University of Agricultural Sciences,Sveriges lantbruksuniversitet,Institutionen för kliniska vetenskaper (KV),Department of Clinical Sciences(Swepub:slu)47499
(author)
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Lohi, Hannes
(author)
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Ruefenacht, Silvia
(author)
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Linek, Monika
(author)
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Paradis, Manon
(author)
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Mueller, Eliane J.
(author)
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Roosje, Petra
(author)
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Leeb, Tosso
(author)
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Uppsala universitetInstitutionen för medicinsk biokemi och mikrobiologi
(creator_code:org_t)
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Sveriges lantbruksuniversitet
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In:PLOS Genetics: Public Library of Science (PLoS)9:10, s. e1003848-1553-73901553-7404
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Wiener, Dominiqu ...
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Welle, Monika M.
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Tengvall, Katari ...
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Bergvall, Kersti ...
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Lohi, Hannes
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Ruefenacht, Silv ...
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Linek, Monika
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Mueller, Eliane ...
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Roosje, Petra
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Leeb, Tosso
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and Pathobiology
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PLOS Genetics
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Uppsala University
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Swedish University of Agricultural Sciences